One of the major problems in hypertension research is the lack of definitive knowledge regarding the mechanism(s) leading to end-organ damage. Vascular remodeling associated with hypertension has been strongly implicated in end-organ damage. The remodeling predisposes to end-organ damage and pharmacological intervention in vascular remodeling should have special clinical efficacy for prevention of hypertensive complications. Therefore, the ultimate goal of this application is to uncover an essential mechanism that initiates hypertensive vascular remodeling as a novel therapeutic target. The renin angiotensin aldosterone system (RAAS) plays critical roles in hypertension and its complications. However, the exact signal transduction mechanism by which angiotensin II (AngII) mediates end-organ damage remains unclear. We have shown that ADAM17, a caveolae-localized metalloprotease, mediates EGF receptor (EGFR) transactivation and subsequent hypertrophic responses in VSMC. Aldosterone (Aldo) is another key factor in the RAAS critically contributing to vascular remodeling and end-organ damage. It has been suggested that the remodeling induced by Aldo involves a non-genomic signal transduction of the mineralocorticoid receptor. Aldo has been shown to transactivate EGFR and subsequently mediate downstream functions in VSMC. Our preliminary data suggest the requirements of ADAM17 and EGFR for AngII-induced vascular mitochondrial dysfunction, ER stress, vascular remodeling and end-organ damage. Our recent publication suggests that a tyrosine kinase is responsible for activation of ADAM17 in VSMC. Using the above information, we have developed the following 2 specific aims to investigate our central hypothesis: AngII and Aldo share a signal transduction indispensable for hypertensive vascular remodeling and end-organ damage, which is initiated by a caveolae-localized ADAM17 kinase, BMX, and amplified by a feed-forward loop including ADAM17, EGFR, ER stress and mitochondrial dysfunction. Aim 1. To explore the downstream mechanism and functional significance of VSMC ADAM17 in mediating hypertensive vascular remodeling (vascular medial hypertrophy and perivascular fibrosis) and end-organ damage induced by the RAAS. Hypothesis: VSMC ADAM17 induction and activation by the RAAS mediate EGFR activation and enhance ER stress and mitochondrial dysfunction, leading to hypertensive vascular remodeling and end-organ damage. Aim 2. To explore the upstream mechanism involved in the novel feed-forward loop of VSMC ADAM17 activation/induction by the RAAS and its consequence for vascular remodeling and end-organ damage. Hypothesis: AngII as well as Aldo activates ADAM17 via BMX, a caveolae-compartmentalized ADAM17 kinase and up-regulates ADAM17 transcriptionally via induction of ER stress and mitochondrial dysfunction in VSMC, leading to vascular remodeling and end-organ damage.